This project will explore the role of macrophages in the pathogenesis of chronic in organ transplantation. We hypothesize that HLA class I and/or II antigens are expressed by cells in the graft serve as the ligand for anti- donor MHC antibodies to be deposited. We speculate that recipient macrophages are stimulated by these antibodies to produce and secreted TGF-beta that appears to be important in organ acceptance. Consistent with this hypothesis, we found that deposited IgG stimulates human monocytes to produce TGF-beta, although whether this TGF-beta is activated is not clear. Thus, we will seek to define how monocyte production of TGF-beta induced by deposited IgG is regulated, determine the biochemical pathways modulating this production, determine if these in vitro data apply to endomyocardial biopsies from patients with heart transplants and test "proof of concept" studies in animal models. This project will interact with the other two projects in the proposal in a manner that will provide additional opportunities for discovery. Through these studies we hope to define the molecular mechanisms by which monocytes, macrophages and IgG may facilitate the generation of chronic rejection in organ transplantation and define new molecular targets to direct new strategies.